The loop-diuretics (ethacrynic acid, furosemide, bumetamide) and aminoglycoside antibiotics (kanamycin, gentamicin, tobramycin, amikacin, etc.) are important drugs frequently used to treat seriously ill patients. Not uncommonly both types of drugs are given to the same patient exposing that patient to the risk of a hearing loss (ototoxicity). This is an insidious adverse drug interaction for two reasons: (1) single doses of the two drugs in combination can produce it, whereas single doses of either alone do not; (2) the ototoxicity may occur even though many hours separate the administration of the two drugs. The long term objectives of this research proposal are to bring sufficient understanding to the cause of this interaction to allow the rational design of means to reduce or eliminate the ototoxicity it produces. We propose to accomplish this using the guinea pig as a model of human cases of the interaction. In addition, ethacrynic acid (EA) and kanamycin (KAN) will be used as prototype drugs. We propose four major studies: (1) measure EA and KAN levels at the site of damage in the interaction; namely, cochlear tissues, to test our hypothesis that EA causes a marked increase in KAN penetration into cochlear hair cells and that ultimately KAN is responsible for the hair cell death and deafness; (2) complement study (1) by correlating KAN levels in cochlear tissues with the amount of hair cell loss after an interaction; (3) test a method of reducing the risk of ototoxicity by reducing the rate of administration of EA; and (4) test whether or not loud noise which can also cause hair cell damage potentiates the ototoxicity caused by the interaction. Noise in the environment may be an unrecognized contributing factor in the loop-diuretic-aminoglycoside antibiotic interaction.